We have been following-up association signals from our prior 100K genome-wide association study (GWAS) in Pima Indians. More than 5035 SNPs have been individually genotyped for fine-mapping in several genomic regions. Within the past year we assembled two large population-based samples of Pima Indians from the Gila River Indian Community for replication of our GWAS signals. The first sample consisted of 3501 full heritage Pima Indians (median age = 39 years with a prevalence of diagnosed diabetes = 45%). The second sample consisted of 3723 subjects who were predominately of mixed heritage (median age = 23 years with a prevalence of diagnosed diabetes = 20%). To date we have genotyped nearly 2700 SNPs in the full heritage sample (N=3501) and 400 SNPs have been further genotyped in the mixed heritage sample (N=2723). We are also comparing our best GWAS signals in Pima Indians with GWAS signals obtained in other populations (predominately Caucasian populations who have submitted their results to public databases). We identified variants near the NELL-1 gene that are strongly associated with diabetes in full-heritage Pima Indians as well as Caucasians. However, our strongest GWAS signals appear to be for the phenotype of BMI rather than diabetes. For example we have identified common variation in the Map2K3 gene that is strongly associated with BMI in both full heritage and mixed heritage populations. We have found that a large portion of this gene has undergone a duplication and we are currently investigating whether one or both genes are functional. We have additionally found variation in the A2BP1 gene that is highly associated with BMI in full heritage Pima Indians and French Caucasian adults. Follow-up studies of our GWAS also identified a variant unique to Pima Indians in the orexin receptor 2 gene that is highly associated with body weight. This gene has a known role in appetite regulation and satiety.